Recently a semiempirical method has been proposed by Aqvist et al. to calculate absolute and relative binding free energies. We are investigating how the optimal value of Delta depends on the nature of binding sites for different protein-ligand interactions. By examining seven ligands interacting with five proteins, we have discovered a linear correlation between the value of Delta and the weighted non-polar desolvation ratio (WNDR), with a correlation coefficient of 0.96. Thus the LIE method can be expected to be more widely used in finding novel leads for ligands that bind tightly to macromolecules.